A novel small molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vivo


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CR Ireson1, KB Harikumar2, AB Kunnumakkara2, A Deorukhkar2, Z Tong2, S Jamieson1, R Sutherland1, T Raynham1, M Charles1, A Bagherzadeh1, M Farooq1, D Maru2, P Diagaradjane2, Y Matsuo2, S Krishnan2, J Gelovani2, BB Aggarwal2, S Guha2

1Wolfson Institute for Biomedical Research, London, UK, 2The UT MD Anderson Cancer Center, Houston, USA

Abstract

Proffered paper presentation

Protein kinase D (PKD) is a novel family of serine-threonine kinase with diverse biological functions prominent amongst which are cell proliferation and growth. Pancreatic cancer (PaCa) is a devastating disease with few therapeutic options. We showed earlier that PKD signalling pathways promote mitogenesis in multiple PaCa cell lines. However, little is known about targeting biological functions of PKD in PaCa.

Our PKD inhibitor discovery program yielded CRT0066101 that specifically blocks PKD activation. The objectives of our study were to determine the effects of CRT0066101 in PaCa, both in vitro and in vivo. Our immunohistochemical analysis showed that activated PKD (pS916PKD1) is significantly upregulated in PaCa as compared to normal ducts (91% vs 22%; p<0.001). Using Panc-1 as a model system, we demonstrated that CRT0066101 blocked proliferation and BrdU incorporation with an IC50 of 1 M. We showed that CRT0066101 given orally (80 mg/kg/day) for 4 weeks significantly abrogated growth in a subcutaneous Panc-1 xenograft model (n=8; p<0.01). The expression of activated PKD (pS916PKD1) in the treated tumour explants was significantly inhibited (p<0.05) with peak plasma concentration (12 M) of CRT0066101 achieved within 6 hours of oral administration.

Further, we showed that CRT0066101 given orally (80 mg/kg/day) for 21 days in an orthotopic model potently blocked Panc-1 tumour growth (n=7; p<0.01). CRT0066101 significantly reduced Ki-67+ proliferation index (p< 0.01), increased apoptosis (measured by in situ TUNEL assay) of PaCa tumors (p<0.05) and potently abrogated expression of multiple proliferative and pro-survival proteins including Cyclin D1, survivin, Bcl-2, Bcl-xL, activated PKD1 (pS916PKD1), and activated PKD2 (pS876PKD2).

Our results demonstrate, for the first time, that the PKD-specific small molecule inhibitor CRT0066101 blocks PaCa growth both in vitro and in vivo. Thus, PKD is a novel therapeutic target in PaCa.